Nickel-catalyzed double bond transposition of alkenyl boronates for in situ syn-selective allylboration reactions

Article abstract of DOI:10.1021/acs.orglett.5b03585

The transposition of a homoallyl pinacol boronic ester was realized by a highly reactive nickel-catalyst system comprising NiCl₂(dppp), zinc powder, ZnI₂, and Ph₂PH. The in situ generated Z-crotyl pinacol boronic esters were reacted with various aldehydes to form syn-homoallylic alcohols in high diastereoselectivities. The present nickel-catalyzed reaction is complementary to the iridium-catalyzed transposition reported by Murakami leading to the corresponding anti-homoallylic alcohols. Also, the multiple transposition of pentenyl pinacol boronic ester was realized.

Full text of DOI:10.1021/acs.orglett.5b03585

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Double Bond Transposition of Alkenyl Boronates
for in Situ syn-Selective Allylboration Reactions
Felicia Weber, Monika Ballmann, Corinna Kohlmeyer, and Gerhard Hilt*
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Straße 4, D-35043 Marburg, Germany
̈
S
* Supporting Information
ABSTRACT: The transposition of a homoallyl pinacol boronic ester was
realized by a highly reactive nickel-catalyst system comprising NiCl2(dppp), zinc
powder, ZnI2, and Ph2PH. The in situ generated Z-crotyl pinacol boronic esters
were reacted with various aldehydes to form syn-homoallylic alcohols in high
diastereoselectivities. The present nickel-catalyzed reaction is complementary to
the iridium-catalyzed transposition reported by Murakami leading to the
corresponding anti-homoallylic alcohols. Also, the multiple transposition of
pentenyl pinacol boronic ester was realized.
he transposition of a carbon−carbon double bond by
Ttransition metal catalysts along a carbon chain can be
achieved in two different ways. The double bond migrates
either toward or away from a functional group.1 Accordingly, an
E-crotyl boron reagent (E-2) could be generated either from a
homoallylic boronic ester (1) when transposition of the double
bond is realized toward the boron functionality or from a vinyl
boronic ester (3) away from the boronic ester group.2 The
latter was demonstrated recently by Murakami utilizing iridium
catalysts.3 The in situ allylboration of aldehydes then generated
the anti-homoallylic alcohols (anti-4) in excellent yields and
diastereoselectivities (Scheme 1).3
(1).4 Accordingly, we envisaged a transition-metal-catalyzed
transposition of a double bond of a homoallylic boronic ester 1
in the presence of an aldehyde so that the reactive allyl boronic
ester species 2 is quenched in situ for the formation of the
desired syn-4 product before another isomerization toward 3
could occur. For a successful and synthetically useful reaction of
this type, three prerequisites must be fulfilled: first, the
isomerization must be diastereoselective toward a defined
double bond configuration of Z-2. Second, the isomerization
must not be inhibited by the present aldehyde. Third, for
achieving a high diastereoselectivity of the allylation reaction,
the isomerization as well as the allylation must be performed at
low temperatures.5
Scheme 1. Outline of Double Bond Transpositions of
Boron-Functionalized Alkenes (Pin = pinacol)
Under these circumstances, our previously described cobalt
catalyst system will not be applicable, since the isomerization
only takes place at room temperature and under these reaction
conditions the allylboration will not be highly diastereoselec-
tive.6 On the other hand, the corresponding nickel-catalyzed
transposition process seems to be well suited for this
transformation.4
When benzaldehyde was reacted with homoallyl boronic
pinacol ester 1 in the presence of the simple and easy to handle
nickel catalyst precursor NiCl2(dppp) (dppp = 1,3-bis-
(diphenylphosphino)propane), which was activated by zinc
powder, zinc iodide, and diphenylphosphine, the desired
product syn-4a could be obtained in 81% yield (Scheme 2).
Some aspects should be noted. For once, the reaction could
also be accomplished in the absence of zinc iodide, but in this
case the reactivity was slightly lower. As we reported before, the
diphenylphosphine was crucial for the reaction. The trans-
position was performed at a temperature as low as −50 °C. At
this temperature, the allylboration readily took place and gave
the desired product syn-4a in good yield and an excellent
diastereoselectivity of 98:2. This indicated that the two
The presence of the aldehyde is tolerated, because there is
essentially no reactivity of homoallyl boronic esters (1) toward
aldehydes. The allyl boron reagent Z-2 will react readily with
aldehydes whereas vinyl boronic esters (3) are unreactive
toward aldehydes as well.
In this report, we describe the complementary allylation of
aldehydes via Z-crotyl boronic esters (Z-2) in which the latter
were generated in situ under mild reaction conditions by a
nickel catalyzed transposition from homoallylic boronic esters
Received: December 17, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b03585
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Organic Letters
Letter
Scheme 2. Nickel-Catalyzed Transposition/Allylation of
Benzaldehyde (Pin = pinacol)
Table 1. Results of the Nickel-Catalyzed Transposition/
a
Allylation Sequence
processes, the nickel-catalyzed isomerization as well as the
allylboration, were highly diastereoselective. As mentioned
above, syn-4a was generated predominantly, thereby indicating
that also in the presence of benzaldehyde, which obviously did
not inhibit the isomerization reaction, the isomerization gave
the Z-isomer of type 2 in high excess. The low temperatures
also prohibited a nickel-catalyzed isomerization of the
homoallylic alcohol 4a toward an allylic alcohol. These results
prompted us to investigate a number of functionalized
aldehydes in the nickel-catalyzed transposition/allylation
process in order to identify the scope and limitations. The
results of these reactions are summarized in Table 1.
Besides the Ph2PH, which had to be kept under oxygen-free
conditions, the other components of the catalyst system are
easy to handle as well as rather inexpensive compared to other
catalyst systems utilizing other metals and additives.1−4
Functional groups such as a methoxy group (4b), halide
functionalities (4c and 4d), a trifluoromethyl group (4e), and a
nitro substituent on the benzene ring (4f) are well accepted and
do not interfere with the nickel-catalyzed isomerization process.
Also, heterocycles, such as thiophene (4h) and α,β-unsaturated
aldehydes (4g), are tolerated. The products 4a−4g were
obtained in good overall yields, and the syn-products were often
formed with a high degree of diastereoselectivity (>92:8). Only
the product derived from thiophene-2-carbaldehyde (4h) led to
a lower yield of 56% and an inferior diastereoselectivity of only
86:14. Noteworthy is the observation that the carbon−carbon
double bonds were not found to undergo a hydrophosphony-
lation which would have consumed the HPPh2. Also, the
aliphatic aldehyde octanal led to the desired product 4i, which
was isolated in a good yield of 78%; however, the determination
of the diastereoselectivity of the overall process was problem-
a
Reaction conditions: NiCl2(dppp) (10 mol %), Zn, ZnI2 (20 mol %
each), Ph2PH (5 mol %), 1 (0.5 mmol, 1.0 equiv), CH2Cl2; different
reaction temperatures and times are listed in the table. The reaction
temperature was adjusted with a dry ice/isopropanol bath. The syn/
1
atic, since diagnostic H NMR signals overlapped significantly.
1
Nevertheless, we estimate the diastereoselectivity for the
formation of 4i to be >95:5 (GCMS analysis). Besides the
products of type 4, no other side products generated by follow-
up transposition reactions were detected at these low
temperatures. Accordingly, the methyl substituent in 4 inhibits
coordination to the nickel catalyst or the hydrogen transfer of
the sterically more hindered 4 is hampered at low temperatures
which allows the selective formation of products 4. When the
reaction toward 4a was performed at +40 °C, follow-up
transpositions toward vinyl pinacol boronic ester 3 were
observed (∼14%) indicating that under elevated temperatures a
fast transposition outruns the allylboration reaction. The
product 4a was obtained in moderate yield (27%) but lower
diastereoselectivity (syn/anti = 80:20). However, transposition
of 4a toward a corresponding allylic alcohol was not observed.
In a second set of experiments, we were interested in
investigating if the double bond transposition process could
also be performed with more complicated homoallylic pinacol
boronic esters (Scheme 3). Therefore, the phenyl-substituent
starting material 5 or homoallylic starting material 7 with
substituent R1 was used to investigate the influence. At this
anti ratios were determined by H NMR spectroscopy.
point we would like to comment that the corresponding cobalt-
catalyst system for the transposition of double bonds for the
latter type of substrates proved to be unreactive.
The choice for the phenyl substituent at the α-carbon was
rationalized by the expectation that the phenyl would
preferentially adopt an E-configuration in the corresponding
product 6 in order to minimize the number of stereoisomers
formed in the reaction sequence. The substituent R1 (7) was
chosen to be a hydrogen and a methyl group for two instances.
Initially, we intended to investigate the possibility of realizing
an isomerization of an exo-chain double bond toward the boron
functionality and thereby generate a geminal-dimethyl subunit
(7a, R1 = H).5 If R1 was not hydrogen but a different group,
such as a methyl group, an interesting scenario would occur.
The introduction of an ethyl group (7b, R1 = CH3) would allow
the formation of a quaternary chiral carbon center in the
proposed product 8. Also the nickel-catalyzed transposition
could either proceed toward the boron functional group to
B
DOI: 10.1021/acs.orglett.5b03585
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Organic Letters
Letter
Scheme 3. Transposition/Allylation of Substituted
Homoallyl Boronic Esters (Pin = pinacol)
Table 2. Results of the Nickel-Catalyzed Transposition of
Substituted Allyl Boronic Esters and Exo-Chain Double
a
Bonds
generate the proposed intermediate 9/10 or lead to
intermediate 11. While 9/10 would react with aldehydes to
generate 8, intermediate 11 would probably resemble a dead-
end and lead to a dramatic loss in efficiency. Both intermediates
possess a trisubstituted double bond that likely does not exhibit
a significant reactivity for the nickel catalyst or a driving force
toward one or the other transposition to convert 9/10 into 11,
or vice versa might be found. The results of these nickel-
catalyzed reactions are summarized in Table 2.
The reaction of 5 led exclusively to the E-configured 6 in
excellent yield (97%) in very good diastereoselectivity (95:5).
The exo-chain double bond derivatives 7a and 7b reacted very
slowly in the cold; however, at room temperature after
somewhat longer reaction times, the desired homoallylic
alcohols of type 8 were obtained in acceptable yields.
Noteworthy, the natural product artemisia alcohol 8c could be
isolated in 80% yield. Moreover, the transpositions of starting
material 7b gave the anti-configured products 8e−8f predom-
inantly. The rationale for the formation of the anti-products is
that the transposition proceeds predominantly via intermediate
10; however, the diastereomeric ratios are only moderate.
Finally, we were interested in investigating if the double bond
transposition could be realized along a longer carbon chain
under relatively mild reaction conditions. This would allow the
introduction of longer alkyl substituents other than a simple
methyl group next to the hydroxyl group in 4 (compare
Scheme 2). Accordingly, as a prototype substrate, 1-pentenyl
pinacol boronic ester 12 was reacted with the nickel catalyst
system in the absence of benzaldehyde at low temperature
(−20 °C), and a mixture of homoallylic and allylic pinacol
boronates were detected (Scheme 4). In the presence of
benzaldehyde even at temperatures, as low as −20 °C, the
double bond transposition proceeded twice and the desired
product 13 could be obtained in an acceptable yield of 72% and
diastereoselectivity (91:9).
a
Reaction conditions: NiCl2(dppp) (10 mol %), Zn, ZnI2 (20 mol %
each), Ph2PH (5 mol %), 5 or 7a/b (0.5 mmol, 1.0 equiv), CH2Cl2;
different reaction temperatures and times are listed in the table. The
reaction temperature was adjusted with a dry ice/isopropanol bath.
Unreacted starting material and other isomers were not separated and
are included in the yield. Conversion were determined by GC/MS
1
analysis, and syn/anti ratios were determined by H NMR spectros-
copy.
Scheme 4. Double Bond Transposition/Allylation of
Benzaldehyde and Pentenyl Pinacol Boronic Ester 12 (Pin =
pinacol)
lower diastereoselectivities. Finally, the nickel-catalyzed isomer-
ization of a pentenyl pinacol boronic ester was performed and
led to the introduction of an ethyl group with good
diastereoselectivity.
In conclusion, we were able to apply the nickel-catalyzed
double bond transposition reaction in the presence of
aldehydes at low temperatures. Thereby the desired homoallylic
alcohols were generated in good yields and high diastereose-
lectivities without further transposition of the double bonds.
Also, exo-chain double bonds could be isomerized, but in these
cases the anti-products were formed predominantly albeit in
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03585.
■
S
Synthesis, analytical data, NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.5b03585
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Organic Letters
Letter
1990, 62, 1993. (g) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986,
119, 1039−1053.
AUTHOR INFORMATION
■
Corresponding Author
(6) The identical reaction performed with CoBr2(dppp) instead of
the nickel catalyst in the presence of benzaldehyde at ambient
temperatures gave no conversion while in the absence of the aldehyde
*E-mail: Hilt@chemie.uni-marburg.de.
Notes
a transposition occurs; see: Schmidt, A.; Nodling, A. R.; Hilt, G.
̈
Angew. Chem., Int. Ed. 2015, 54, 801−804.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the German Science Foundation (Hi655 17-1) for
financial support.
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